rs35544003

Variant names:

• chr14-76439434-C-A
• rs35544003
• NM_001379180.1:c.144C>A

Your query was ambiguous. Multiple possible variants found:

• chr14-76439434-C-A
• chr14-76439434-C-G
• chr14-76439434-C-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001379180.1(ESRRB):​c.144C>A​(p.Ile48Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0647 in 1,613,444 control chromosomes in the GnomAD database, including 4,914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (605 hom., cov: 33)
  • Exomes 𝑓: 0.063 (4309 hom.)
• Consequence: ESRRB NM_001379180.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.310
• Publications: 17 publications found

Genes affected

ESRRB (HGNC:3473): (estrogen related receptor beta) This gene encodes a protein with similarity to the estrogen receptor. Its function is unknown; however, a similar protein in mouse plays an essential role in placental development. [provided by RefSeq, Jul 2008]

ESRRB Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 35

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 14-76439434-C-A is Benign according to our data. Variant chr14-76439434-C-A is described in ClinVar as Benign. ClinVar VariationId is 45001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379180.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESRRB	NM_001379180.1	MANE Select	c.144C>A	p.Ile48Ile	synonymous	Exon 2 of 7	NP_001366109.1
	ESRRB	NM_004452.4		c.81C>A	p.Ile27Ile	synonymous	Exon 4 of 11	NP_004443.3
	ESRRB	NM_001411038.1		c.96C>A	p.Ile32Ile	synonymous	Exon 2 of 7	NP_001397967.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESRRB	ENST00000644823.1	MANE Select	c.144C>A	p.Ile48Ile	synonymous	Exon 2 of 7	ENSP00000493776.1
	ESRRB	ENST00000509242.5	TSL:1	c.81C>A	p.Ile27Ile	synonymous	Exon 2 of 9	ENSP00000422488.1
	ESRRB	ENST00000505752.6	TSL:1	n.81C>A		non_coding_transcript_exon	Exon 4 of 12	ENSP00000423004.1

Frequencies

GnomAD3 genomes AF: 0.0762 AC: 11603 AN: 152184 Hom.: 601 Cov.: 33

Gnomad AFR AF: 0.0918

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0855

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.0526

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0537

Gnomad OTH AF: 0.0626

GnomAD2 exomes AF: 0.0869 AC: 21504 AN: 247442 AF XY: 0.0861

Gnomad AFR exome AF: 0.0902

Gnomad AMR exome AF: 0.0905

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.249

Gnomad FIN exome AF: 0.0570

Gnomad NFE exome AF: 0.0574

Gnomad OTH exome AF: 0.0681

GnomAD4 exome AF: 0.0635 AC: 92781 AN: 1461142 Hom.: 4309 Cov.: 36 AF XY: 0.0652 AC XY: 47392 AN XY: 726870

African (AFR) AF: 0.0905 AC: 3031 AN: 33476

American (AMR) AF: 0.0885 AC: 3956 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 632 AN: 26130

East Asian (EAS) AF: 0.247 AC: 9818 AN: 39692

South Asian (SAS) AF: 0.134 AC: 11527 AN: 86246

European-Finnish (FIN) AF: 0.0590 AC: 3125 AN: 52946

Middle Eastern (MID) AF: 0.0347 AC: 200 AN: 5764

European-Non Finnish (NFE) AF: 0.0505 AC: 56137 AN: 1111806

Other (OTH) AF: 0.0721 AC: 4355 AN: 60370

GnomAD4 genome AF: 0.0764 AC: 11633 AN: 152302 Hom.: 605 Cov.: 33 AF XY: 0.0799 AC XY: 5950 AN XY: 74474

African (AFR) AF: 0.0921 AC: 3830 AN: 41568

American (AMR) AF: 0.0856 AC: 1310 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3470

East Asian (EAS) AF: 0.256 AC: 1323 AN: 5158

South Asian (SAS) AF: 0.137 AC: 662 AN: 4824

European-Finnish (FIN) AF: 0.0526 AC: 559 AN: 10630

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0537 AC: 3654 AN: 68028

Other (OTH) AF: 0.0619 AC: 131 AN: 2116

Alfa AF: 0.0546 Hom.: 105

Bravo AF: 0.0757

Asia WGS AF: 0.195 AC: 676 AN: 3478

EpiCase AF: 0.0455

EpiControl AF: 0.0439

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Autosomal recessive nonsyndromic hearing loss 35 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	4.4
DANN	Benign	0.91
PhyloP100		-0.31
PromoterAI		-0.021	Neutral
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35544003; hg19: chr14-76905777; COSMIC: COSV55058640; COSMIC: COSV55058640;